Investigation of triple-negative breast cancer risk alleles in an International African-enriched cohort

Rachel Martini,Melissa B Davis,Lindsay F Petersen,Michael O Adinku,Kofi K Gyan,Joseph K Oppong,Francis Aitpillah ,Brittany D Jenkins,Baffour Awuah,Esther Cheng,Yalei Chen,Dhananjay Chitale,Rick A Kittles ,Paula Ginter ,Rozina Zeidan ,Jeffrey Hanover,Jessica Bensenhaver ,Ernest Adjei ,Engida Abebe,Isra Elhussin ,Clayton Yates,Evelyn Jiagge,Saul David Nathansan,Aisha Jibril,Ishmael Kyei,Lisa A Newman,Syed A Hoda,Kwasi Ankomah,Ernest Osei‐Bonsu ,Mahteme Bekele,La Toya Jackson ,Petros Nikolinakos,Erica Proctor

doi:10.1038/s41598-021-88613-w

Abstract

Large-scale efforts to identify breast cancer (BC) risk alleles have historically taken place among women of European ancestry. Recently, there are new efforts to verify if these alleles increase risk in African American (AA) women as well. We investigated the effect of previously reported AA breast cancer and triple-negative breast cancer (TNBC) risk alleles in our African-enriched International Center for the Study of Breast Cancer Subtypes (ICSBCS) cohort. Using case–control, case-series and race-nested approaches, we report that the Duffy-null allele (rs2814778) is associated with TNBC risk (OR = 3.814, p = 0.001), specifically among AA individuals, after adjusting for self-indicated race and west African ancestry (OR = 3.368, p = 0.007). We have also validated the protective effect of the minor allele of the ANKLE1 missense variant rs2363956 among AA for TNBC (OR = 0.420, p = 0.005). Our results suggest that an ancestry-specific Duffy-null allele and differential prevalence of a polymorphic gene variant of ANKLE1 may play a role in TNBC breast cancer outcomes. These findings present opportunities for therapeutic potential and future studies to address race-specific differences in TNBC risk and disease outcome.

Highlights

Large-scale efforts to identify breast cancer (BC) risk alleles have historically taken place among women of European ancestry
Our overall BC risk assessment model was an all-inclusive analysis, including all breast cancer subtypes and self-indicated race (SIR)/ancestral groups, where we have expanded the number of BC cases from Eastern and Western African nations, investigating previously published BC risk alleles that have been validated among African American women in the AMBER consortium[32] (Tables 1, 2, Fig. 1A)
We found that the T allele of rs2981578 in the FGFR2 gene was associated with increased risk (OR = 1.508, p = 0.008491), which contrasts with previous reports of the C allele as the risk allele

Summary

Introduction

Large-scale efforts to identify breast cancer (BC) risk alleles have historically taken place among women of European ancestry. Population studies of hormone receptor (HR) status in breast cancer diagnoses indicates a two-fold increased risk of Triple Negative Breast Cancer (TNBC) in AA compared to EA patients, which persists after adjusting for stage and age at d iagnosis[5,6,7,8] This trend extends beyond certain social determinants, with AA having the highest rate of TNBC at every poverty level as well[9]. There is a severe shortage of genetic and GWAS data in non-white populations[13,14], where less than 10–15% of individuals in population studies are Black, Indigenous, and People of Color (BIPOC), if race or ethnicity groups are reported at a ll[13] This tragic limitation stifles our efforts to identify population-specific risk alleles outside of European descendant groups. These efforts will provide further evidence and methodological insight in the role of shared African ancestry in the shared racial disparity of TNBC incidence across the African diaspora

Methods

Results

Conclusion